Perinatal brain damage and subsequent neurological dysfunction are disorders with complex etiology. Over the past three decades, the recognized causal paradigm has shifted from exclusively hypoxic-ischemic causation at, around, or after birth to include infection/inflammatory mechanisms. Using an intracerebral (i.c) injection of lipopolysaccharide (LPS) in the neonatal rat brain as a model, we have shown that LPS and inflammatory cytokines play critical roles in mediating white matter injury in the neonatal brain. Our results further indicate that adverse effects of perinatal infection may be far more than those observed in the neonatal and juvenile stages. It may also contribute to the occurrence of late-onset neurodegenerative diseases. It has been reported that prenatal exposure to LPS is linked with loss of dopaminergic (DA) neurons in the offspring brain at adult stages, a hallmark of Parkinson[unreadable]s disease (PD) which is a neurodegenerative disease typically seen in aged people. However, our preliminary results show that perinatal LPS exposure causes decreased expression of tyrosine hydroxylase in DA neurons, but not the actual death of DA neurons in the substantial nigra (SN). Our data further show that perinatal exposure to LPS enhances susceptibility of DA neurons in the SN in the adult brain to an ordinarily non-toxic or sub-toxic dose of rotenone, resulting in actual loss of DA neurons and development of PD-like symptoms. Based on these observations, we hypothesize that perinatal exposure to LPS may result in chronic inflammation and prolonged exposure to such an environment may enhance vulnerability of DA neurons in the SN of adult brain to an ordinarily non-toxic or subtoxic dose of neurotoxin to develop PD-like symptoms, and that the long-term effect of perinatal LPS exposure is mediated, at least partially, by a sustained elevation in IL-1beta level, phosphorylated P38 MAPK (pP38) and microglia activation in the SN. The following specific aims will be addressed: Aim #1: to test this hypothesis with another environmental toxin, paraquate, at an ordinarily non-toxic or sub-toxic dose and to characterize the chronic inflammatory conditions in the SN following perinatal exposure to LPS and correlate the enhanced vulnerability of the DA neurons to a sub-toxic dose of rotenone with the chronic inflammatory condition. Aim #2: to determine the role of sustained elevations in IL-1beta and pP38 following perinatal LPS exposure on enhancement of DA neuron vulnerability to a sub-toxic dose of rotenone at adult stages through i.c. injection of IL-1beta or co-administration of LPS with an IL- 1 receptor antagonist or inhibitors of P38 MAPK and then compare the impairment of DA neurons and motor dysfunctions following administration of a sub-toxic dose of rotenone in late life. Aim #3: to determine the role of sustained activation of microglia following perinatal LPS exposure on enhancement of DA neuron vulnerability to rotenone toxicity, using minocycline, an inhibitor of microglia activation, in vivo or in co-cultures of microglia with rat mesencephalic neurons grown on a monolayer of astrocytes. Results from the proposed studies will enhance our understanding of mechanisms involved in long-term adverse effects of perinatal brain inflammation on late-onset neurodegenerative diseases and provide information for developing preventive strategies against these adverse effects.